Phospholipase A2 (PLA2; EC 3.1.1.4) is a general term of phospholipids-cleaving enzyme that hydrolyzes the 2-acyl ester bond of 3-sn-phosphoglyceride. PLA2 is involved in the digestion of phospholipids in food and the generation and metabolism of phospholipids in the cell membranes. In addition, PLA2 plays as a rate-limiting enzyme of the arachidonic acid cascade in the production of lipid mediators including prostaglandins. It has been known that various types of PLA2s exist in mammals. PLA2s are classified into 4 different families, such as the secretory PLA2, cytosolic PLA2, Ca2+-independent PLA2, and platelet-activating factor-acetylhydrolase, based on the localization, Ca2+ requirement, and substrate specificity (Balsinde et al., J. Biol. Chem. 272, 16069-16072 (1997)).
Among them, secretory PLA2 family comprises PLA2 enzymes that are secreted into the outside of the cells and have a relatively low molecular weight (13,000-15,000). As the member of the family, 5 types including IB type, IIA type, IIC type, V type, and X type, have been already identified. Each molecule has 12 to 16 Cys residues that form disulfide-bonds in the molecule, and possesses a consensus active site consisting of His-Asp residues. In addition, the molecules have a common Ca2+ binding region. Micro mole order of Ca2+ concentration is required for the exertion of the enzymeactivity (Tischfield et al., J. Biol. Chem., 272, 17247-17250 (1997), Cupillard et al., J. Biol. Chem., 272, 15745-15752 (1997)).
It is assumed that IB type has a function as a digestive enzyme in the pancreas etc. and is involved in the progression of inflammation, such as endotoxin shock, through the binding to its specific receptor. It is also assumed that IIA type plays a role in various inflammatory responses because this type is expressed in blood platelets and synovial cells etc., and its expression is elevated during stimulation of inflammatory cytokines. However, the inflammatory response is normal in genetically IIA-deficient mice. Thus, its pathological significance remains unresolved. V type is expressed in the heat and several inflammatory cells. X type is expressed in the tissues related to the immunity such as spleen and thymus. Although it is suggested that both types are involved in the bio-regulation and inflammatory response, their importance in the body has not been clearly identified (Hanasaki et al., Cell Technology, 17, 694-701 (1998)).